Genetic Map/Route of the Cardiovascular System

Before we move to the final step in The DNA Company’s assay design, let’s take a break and consider a scenario:

Callum and McKenzie are life long buddies. They are of similar age, body type and weight. They grew up in a small mining town and like their forefathers, eke out a living through the local mining industry. Hard work means that despite a standard American diet, they are lean and strong. They shop at the same grocery stores, take the same cigarette breaks, hang with the same crowd on Friday and Saturday nights for one beer too many. Yearly medical exams are a luxury that belongs to the ‘other’...not Callum and McKenzie. They’re both made of ‘tough stuff’. One week from his 49th birthday, Callum suffers a bout of debilitating shortness of breath and excruciating chest pains. Callum suffered his first heart attack. Further clinical work-up indicated multiple points of vascular blockage, clinically elevated blood lipids as well as inflammatory markers. Callum pulls through and his close mate McKenzie was often at his bedside for evening visits. With Callum’s rude awakening, McKenzie’s family chips in and encourages him to see a doctor for a full physical exam. He’s given a complete and clear bill of health. He passed with flying colors. His doctor could not believe he does what he does for a living, or his nutritional and lifestyle choices.

What differentiates Callum from McKenzie? After all, they’ve been best buds and neighbors since grade school. They were best men at each other’s weddings. They work at the same place, eat the same food, share the same environment and lifestyle.

Continue to read now to gain some very telling insights into this all-too-familiar story.

In creating a genetic assay for the CVS, The DNA Company matches the appropriate genes for each detail in the storyboard. In this manner the genomic assay created is exceptionally unique. It actually traces the cellular cascade that culminates in CVD. Notice, that the goal of the assay is not an arbitrary % risk designation, but an actual functional and measurable documentation of cellular events that prelude to cardiovascular disease.

The single most significant genomic markers associated with the CVS are known as the 9p21 genetic markers. Several studies have confirmed that 2 SNPs within these markers statistically significantly increases the risk of multiple CVD outcomes. The at-risk G allele of both 9p21 SNPs seems to increase the sensitivity of the endothelial lining of the vasculature to inflammatory agents within the blood. The latter may include toxins (both endogenous and exogenous), medications and even hormonal factors such as chronically elevated estrogen metabolites. For both SNPs, the ‘G’ allele is the at-risk allele. Risk appears to be on a continuum reflecting the total number of G alleles present, such that:

Risk associated with 4 G alleles > risk associated with 3 G alleles > risk associated with 2 G alleles > risk associated with 1 G allele

Potentially inflammatory blood-borne metabolites will come from several sources, each informed or relevant to its own genetic pathways: i. Organic and inorganic toxins, both exogenous and endogenous, that require genes such as those from the GST family to detoxify and remove from the body ii. Food metabolites such as glucose that will require genes such as TCF7L2 to facilitate an appropriate insulin response iii. Internal cellular metabolites such as 4-hydroxyestrogen produced by the CYP1B1 pathway as part of normal estrogen metabolism are highly variable from person to person.

Methylation is an incredibly important cellular system. It is responsible for a myriad of cellular events. It is a cornerstone of the cell’s ability to reduce or eliminate markers of inflammation. Poor methylation has been strongly associated with vascular disease for the very reason that once inflamed, the vascular endothelium relies on methylation to stem the inflammatory cascade. The methylation pathway or system has been thoroughly studied and mapped. The genes involved are well-known and sequenced. Important SNPs in each of the genes involved in methylation determine the unique methylation (and hence anti-inflammatory) capacity of an individual.

Many, including clinicians, are surprised to learn that one of the primary signals for the production and secretion of lipids (including cholesterol) into the blood, is inflammation of the endothelium of the blood vessels. Few genes have been studied in relation to cardiovascular disease (especially as related to hypercholesterolemia) as the APOE gene. The e4 subtype of the APOE gene is significantly associated with lipid pathologies and other CVD comorbidities. It appears that the APOE gene plays a significant role in trafficking blood lipids to the vascular endothelium (in response to inflammation)

Once lipids are deposited on to the endothelium, the main concern and next step in the genesis of endothelial dysfunction and plaque production is the oxidation of the lipids. Therefore, anti-oxidative pathways and their corresponding genes play a significant role in predicting the individual likelihood of this next phase in CVD. Genes such as SOD2 and the previously mentioned GST family are significantly associated with the progression of endothelial dysfunction. Simply stated, poor innate anti-oxidative capacity in the face of chronic endothelial inflammation is not a good combination.


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